DE60217062T2 - PROCESS FOR THE PREPARATION OF CLOPIDOGREL - Google Patents

Abstract

The present invention discloses a process for the preparation of thieno[3,2-c]pyridine derivatives of general formula (I), in either racemic or optically active (+) or (-) forms and their salts, wherein X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine. The present invention also describes a process for preparing the compounds of general formula (II), in either racemic or optically active (+) or (-) forms and their salts, where X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine. The compounds represented by formulae (I) and (II) have one asymmetric carbon and hence, the optically active compounds of formula (I) or of formula (ii), may be obtained either by resolving the racemic intermediate/final product or using an optically active intermediate. The compounds of the invention are pharmacologically active and have significant anti-aggregating and anti-thrombotic properties.

Description

Territory of invention

The present invention relates to a process for the preparation of thieno [3,2-c] pyridine derivatives of the general formula (I) in racemic or optically active (+) or (-) - forms and their salts, wherein X, the Substituent on the benzene ring, either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine.

Preferably X represents 2-chloro.

The present invention further describes a process for preparing compounds of the general formula (II) in racemic or optically active (+) or (-) forms and salts thereof, wherein X, the substituent on the benzene ring, is either a hydrogen or a halogen atom such as fluorine, chlorine, bromine or iodine.

Preferably X represents 2-chloro. These compounds are suitable intermediates for the preparation of compounds of general formula (I).

The of formula (I) and (II) have an asymmetric Carbon, and as a possibility to obtain optically active compounds of the formula (I) or the Formula (II) is therefore available either dissolve the racemic intermediate / final product or to use an optically active intermediate.

GENERAL STATUS OF THE TECHNOLOGY

In FR 2,215,948 . FR 2,530,247 and FR 2,612,929 Thieno [3,2-c] pyridine derivatives described are pharmacologically active and have considerable anti-aggregation and anti-thrombosis properties. One such example is "clopidogrel", (S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetic acid methyl ester, and its pharmaceutically Later, it was found that only the (S) (+) stereoisomer is biologically active ( US 4,847,265 ). Because "clopidogrel base" is an oily liquid, the base is converted to a pharmaceutically acceptable salt to produce a convenient formulation Suitable salts of "clopidogrel base" can be formed with taurocholate, hydrobromide and sulfuric acid.

Reported methods for synthesizing compounds of general formula (I) ( US 4529596 . GB 0420706 and GB 0466569 ) use α-halophenylacetic acid derivatives which are tearing and irritating in nature. Methods for synthesizing such compounds involve several steps and have other disadvantages due to the chemicals / reagents used, which are generally difficult to handle and scale up and are not conducive to human health and the environment. In addition, the yields of these processes are poor to mediocre. Various other synthetic approaches found in the literature include expensive or hazardous chemicals that do not significantly improve the yield of the desired product.

Recently, radioactively labeled (Bezen-U- ¹³ C) racemic (±) clopidogrel was used as the standard for me Tabolische studies with a total yield of 7 using an ortho-preparation / chlorination of benzoic acid derivatives prepared (Burgas et al., J. Labeled Cpd Radiopharm, 43, 891-898 (2000)). This paper discusses the synthesis of clopidogrel in the presence of acetone cyanohydrin. Various other strategies are described in: WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, US 4,876,362 . US 5, 036, 156 . US 5, 132, 435 . US 5,139,170 . US Pat. No. 5,204,469 and US Pat. No. 6,080,875 ,

Recently, a patent application (WO 99/65915) has described a novel polymorph of clopidogrel bisulfate (designated Form II) which has a melting point of 176 ± 3 ° C. It also mentions that the methods described in the earlier US patent ( US 4,847,265 ) has another melting point of about 184 ± 3 ° C (now referred to as Form I). Both polymorphs have been shown to have distinct and characteristic XRD and IR spectra.

Therefore The present invention aims to be a cheap and commercial one suitable method for preparing compounds of the formula (I) provide in good yields.

SUMMARY THE INVENTION

The present invention provides a novel process for the preparation of thieno [3,2-c] pyridine derivatives represented by the general formula (I) in racemic or optically active (+) or (-) forms and salts thereof, wherein X represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine.

One embodiment of the present invention provides a process for preparing (S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetic acid methyl ester as Bisulfate salt, ie clopidogrel bisulfate, ready. Preferably, X represents 2-chloro.

Further, the present invention provides a process for the preparation of a compound of formula (II) (2-halophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide in racemic or optically active (+) or (-) forms and their salts. Preferably, X represents 2-chloro.

The Dextroisomers of compounds of formula (II) of suitable purity or their salts are suitable intermediates for the synthesis of (+) - clopidogrel bisulfate.

Another embodiment of the present invention provides a process for the production of a Compound of formula (III), (2-halophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetic acid in racemic (±) or optically active (+) - or (-) - forms and their salts ready.

A another embodiment The present invention provides a method for the production of compounds of formula (IV), (±) - (2-halophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile and their salts ready. Preferably, the halogen is chlorine.

DETAILED DESCRIPTION OF THE INVENTION

The The present invention provides a method of making connections of the formula (I) in racemic or optically active (+) or (-) - form and salts thereof, wherein X is either hydrogen or a halogen atom such as fluorine, chlorine, bromine or iodine. In particular, the Invention a method for producing clopidogrel bisulfate ready.

oder deren Salze in razemischer oder optisch aktiver (+)- oder (–)-Form, wie in Schema 1 ausgeführt.

SCHEMA 1 The process for preparing compounds of the formula (I) or salts thereof uses compounds of the formula (II)

or their salts in racemic or optically active (+) or (-) form, as outlined in Scheme 1.

SCHEMA 1

each Intermediate in Scheme 1 has a chiral center. Therefore, a produce optically active product, for example those of formula Compound (I), especially clopidogrel and its salt it is possible to use an optically active intermediate from the first step.

• 1. Herstellen einer Verbindung nach Formel (IV), (±)-(2-Halogenphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitril wie beschrieben in Schema 2, d. h. über die Strecker-Reaktion;
• 2. Auflösen, falls gewünscht, der razemischen Mischung einer Verbindung der Formel (IV) in ihre optisch aktiven (+)- und (–)-Stereoisomere; und Rückführen des unerwünschten Stereoisomers in das Verfahren durch Razemisierung;
• 3. Transformieren der Verbindung der Formel (IV) in entweder eine razemische oder optisch aktive (+)- oder (–)-Form oder ihr Salz, in die Verbindung der Formel (II), (±)-(2-Halogenphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamid oder eine optisch aktive entsprechende (+)- oder (–)-Form, ausgehend von dem verwendeten Ausgangsmaterial;
• 4. Auflösen, falls gewünscht, der razemischen Verbindung der Formel (II) in ihre optisch aktiven (+)- und (–)-Stereoisomere; und Rückführen des unerwünschten Stereoisomers in das Verfahren durch Razemisierung;
• 5. Transformieren der Verbindung der Formel (II) in entweder eine razemische oder optisch aktive (+)- oder (–)-Form oder ihr Salz, in eine optisch aktive oder razemische Verbindung von Formel (I), (±)-(2-Halogenphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetatmethylester, in eine razemische oder optisch aktive (+)- oder (–)-Form und ihre Salze, ausgehend von dem verwendeten Ausgangsmaterial;
• 6. Des Weiteren Auflösen und/oder Transformieren der razemischen/optisch aktiven Verbindung der Formel (I) in ihre pharmazeutisch annehmbaren Salze und/oder Freisetzung der razemischen oder optisch aktiven Verbindung der Formel (I) aus ihren Salzen.

The present invention provides a process for the preparation of compounds of formula (I) and salts thereof as shown in Scheme 1, the process comprising the steps of:

• 1. Preparation of a compound of formula (IV), (±) - (2-halophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile as described in Scheme 2 ie via the Strecker reaction;
• 2. dissolving, if desired, the racemic mixture of a compound of formula (IV) into its optically active (+) and (-) stereoisomers; and returning the unwanted stereoisomer to the process by racemization;
• 3. Transforming the compound of formula (IV) into either a racemic or optically active (+) or (-) form or its salt, into the compound of formula (II), (±) - (2-halophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide or an optically active corresponding (+) or (-) form, starting from the starting material used;
• 4. Dissolve, if desired, the racemic compound of formula (II) into its optically active (+) and (-) stereoisomers; and recycling the undesired stereoisomer to the process by racemization;
• 5. Transforming the compound of formula (II) into either a racemic or optically active (+) or (-) - form or its salt, into an optically active or racemic compound of formula (I), (±) - (2 -Halo-phenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetate methyl ester, in a racemic or optically active (+) or (-) form and its salts from the starting material used;
• 6. Further dissolving and / or transforming the racemic / optically active compound of the formula (I) into its pharmaceutically acceptable salts and / or liberating the racemic or optically active compound of the formula (I) from its salts.

alternative may be any of the compounds of formula (IV) or (II), either in racemic or optically active (+) - or (-) - form, into corresponding compounds of formula (III), which are then transformed into the corresponding Compound of formula (I) can be converted.

The Compound of formula (IV) in racemic or optically active (+) - or (-) - forms can be converted directly into the corresponding compound of formula (I) become.

Optional can in the above mentioned Process suitable acid addition salts the intermediates of the formula II, III, and IV are used. Suitable acids used can from acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, Methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, camphorsulfonic, Hydrochloric, sulfuric, hydrobromic and the like.

Another aspect of the present invention is to provide a process for the preparation of a novel intermediate of formula (IV) and salts thereof.

SCHEMA 2 Another aspect of the process of the invention involves the preparation of intermediates described by the general formula (IV) and as shown in Scheme 2 by the Strecker reaction using a secondary amine (Organic Synthesis Collective Volume III, page 275).

SCHEMA 2

The A process for preparing compounds of formula (IV) reacting the amine of formula (V) or its salts with a Cyanide derivative of general formula (VII), wherein M is either alkali metals such as Na, K, Li or H, trimethylsilyl (TMS) and the like, with 2-chlorobenzaldehyde of the formula (VI). The synthesis of the amine or its salts of formula (V) is described in FR 2608607.

The The above reaction can be carried out in various ways. Some such procedures are outlined in Scheme 2 shown above. At the beginning, the amine of formula (V) or its salt with cyanide (VII) implemented, where M is as defined above, followed by addition of 2-chlorobenzaldehyde (VI). Alternatively, 2-chlorobenzaldehyde (VI) treated with cyanide of the formula (VII), wherein M is as defined above is, and the intermediate cyanohydrin is further enriched with amine Implemented formula (V) or its salt. In an alternative method 2-chlorobenzaldehyde of the formula (VI) becomes a bisulfite derivative of the formula (VIII) added, wherein M'Na, K, Li and the like; followed by the reaction with cyanide of the formula (VII), wherein M is as defined above, and finally with Amine of formula (V) or its salt in an in situ reaction. Independent of the variants of the reaction procedure, the yield of obtained resulting intermediate (IV) comparable.

The preferred methods include the addition of 2-chlorobenzaldehyde of the formula (VI) to bisulfite derivatives of the formula (VIII). The educated Salt is reacted with cyanide of the formula (VII) and finally with an amine of the formula (V) or its salt in the presence of suitable reagents and solvents treated.

suitable Reagents include acid catalysts such as glacial acetic acid (Synthesis, 1989, 616-618), hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, polyphosphoric acid and like.

Suitable solvents may be hydrophilic solvents, either protic or aprotic, and include water, (C ₁ -C ₄ ) -alcohol, tetrahydrofuran, dimethylformamide, DMSO, dioxane, 1,2-dimethoxyethane, acetic acid, propionic acid and the like, or a mixture of their solvents. The preferred solvent is a mixture of solvents and water in various proportions. The more preferred reaction medium comprises a mixture containing water and (C ₁ -C ₄ ) -alcohol in a ratio between 1: 1 and 1:10.

If the reaction in an aprotic or hydrophobic solvent carried out is a phase transfer catalyst and a two-phase solvent system required. Suitable phase transfer catalysts used in such a case can Tetrabutylammonium halide, Benzyltrimethylammoniumhalogenid and to be like that.

During the Reaction can certain additives are added. Such suitable additives may be cyclo [(S) -histidine (S) -phenylalanine] and the like.

The Reaction temperature can be from -30 ° C to Reflux the solvent (s) used (s) range. The preferred temperature is in the range of 0 ° C to 100 ° C and more preferably from 40 ° C to 80 ° C. If whereas HCN (g) is used (Scheme 2, intermediate VII, M = H), the required temperature is in the range of about -30 ° C to -10 ° C.

This reaction can be carried out in the absence or presence of an inert atmosphere such as N ₂ , He or Ar. The duration of the reaction may vary from 1 hour to 3 days, especially from 2 hours to 2 days.

It is preferred, a compound of formula (V), bisulfite derivative (VIII) and cyanide derivative (VII) relative to 2-chlorobenzaldehyde (VI) in the relationship of preferably between 1 to 1.2 equivalents. The thus obtained racemic cyano compound (IV) can be in optically active (+) - and (-) - forms to be triggered.

The thus obtained cyano compound (IV) can be converted into an appropriate acid of Formula (III), in an amide of the formula (II) or in an acid of Formula (I), as shown in Scheme 1 (R.C. Larrock, in "Comprehensive Organic Transformations ", John Wiley & Sons, Inc, 1999, 2nd edition, 815-818, and references therein).

One Another aspect of the present invention is these intermediates II and III convert compounds of formula I, as in Scheme 1 shown. Each of the (±) -, (+) - or (-) - isomers the intermediate of formula II and III can be converted into the corresponding Isomer of compounds of formula I are converted.

Of the preferred way to obtain the compound of formula (I) the conversion of the (±) -, (+) - or (-) - isomer the cyano compound (IV) and its salts to an amide compound of the formula (II) in the presence of suitable acidic / basic reagents in suitable solvents. Later the amide becomes its optically active (+) or (-) form or its salt dissolved, and the optically active amide becomes an optically active ester of the formula (I) in the presence of a suitable catalyst and reagent transformed.

The reaction for converting a cyano compound of the formula (IV) into an amide compound of the formula (II) may be carried out in the presence of reagents containing an acid or a base. Suitable acids which may be used are acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, chloroacetic acid and the like, or an anhydrous alcoholic or aqueous solution of mineral acids such as sulfuric acid, HCl, HBr and the like. A base is preferred when the starting material is a racemic mixture. Suitable bases which can be used are lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide or a mixture thereof, preferably alkali metal hydroxides. An excess of hydrogen peroxides or metal peroxides in the above reaction may also be used with alkali metal hydroxides. Suitable solvents for the above reaction may be aqueous, polar or protic solvents such as water, (C ₁ -C ₄ ) -alcohol, acetone, acetic acid, dimethylformamide, THF, DMSO, dioxane, DME and the like or mixtures thereof, preferably the solvent from water, methanol or tert-BuOH or a mixture of these solvents in a ratio varying between 1: 1 to 1:10.

The temperature is in the range of 20 ° C to 250 ° C, preferably 50 ° C to 150 ° C. The reagents used in the above process may be in the range of 0.01 to 1.2 molar equivalents. The reaction may be carried out in the absence or presence of an inert atmosphere such as N ₂ , He or Ar. The reactions under the basic conditions preferably proceed in an inert atmosphere. The duration of the reaction may last from ½ hour to 5 days, preferably from 2 hours to 2 days.

The Amide of the formula (II) in racemic or optically active (+) - or (-)-Shape or its salt can be in the presence of at least one equivalent of methanol and acid in a suitable solvent in convert a corresponding methyl ester of formula (I).

Suitable acids that may be used include acetic acid, polyphosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, chloroacetic acid or mineral acids, which include sulfuric acid, HCl, HBr and the like, which may be in various forms such as acid dissolved in alcohol, anhydrous Acids dissolved in or saturated with alcohol, and the alcohol used may be methanol. The preferred acid is concentrated sulfuric acid in an equivalence ratio of 1 to 50. Suitable solvents for the above transformation can be polar or protic solvents such as hydrophilic solvents including methane, acetone, acetic acid, THF, DMSO, dioxane, DME and the like, or mixtures thereof. The preferred solvent is methanol in at least one equivalent and may be present in large excess to act as a solvent. At times, an inert co-solvent such as toluene, xylene, etc. may also be used.

The temperature is in the range of 20 ° C to 250 ° C, preferably 50 ° C to 150 ° C. The reaction may be carried out in the absence or presence of an inert atmosphere such as N ₂ , He or Ar. The duration of the reaction may last from 3 hours to 5 days, preferably from 4 hours to 2 days.

It is possible, the compound of formula (IV) in either racemic or optical active (+) or () form or its salt in the presence of appropriate solvent and reagents into the corresponding acetic acid derivative of the formula (III) convert. Suitable solvents can aqueous or alcoholic type. Suitable reagents for the above Reaction include acids as well as bases.

It is possible, too, the cyano compound of the formula (IV) in either racemic or optically active (+) or (-) - form or their salt in the presence of at least one acid equivalent and at least one equivalent of methanol in suitable solvents according to methods known from the literature directly into the methyl ester of formula (I).

The Acid of Formula (III) in either racemic or optically active (+) - or (-)-Shape or their salts can in the presence of suitable reagents in suitable solvents and at least one equivalent converted from methanol to the corresponding methyl ester of formula (I) become.

suitable Reagents that may be used include thionyl chloride, acid chlorides such as pivaloyl chloride, alkyl chloroformates such as ethyl or methyl chloroformates and other such reagents containing the Activate COOH group in an equivalence ratio of 1: 1. A suitable solvent for the above transformations can be a polar or protic solvent such as methanol, acetone, dimethylformamide, THF, DMSO, Dichloromethane, dichloroethane, dioxane, DME and the like, or mixtures be of it. The preferred solvent consists of methanol in at least one equivalent and can be in such large excess be present as a solvent acts. The temperature is in the range of 20 ° C to 250 ° C, preferably 50 ° C to 150 ° C.

The Reagents used in the above process can range from 0.01 mol up to equimolar conditions available. The reaction can be in the absence or presence of a inert atmosphere like N2, He or Ar performed become. The duration of the reaction can range from 3 hours to 5 days, preferably from 3 hours to 2 days.

• 1) Er erfordert weniger Schritte zur Herstellung der Verbindungen der Formel (I).
• 2) Es werden einfache und leicht erhältliche Reagenzien/Chemikalien verwendet.
• 3) In verschiedenen Schritten werden mildere Reaktionsbedingungen verwendet.
• 4) Es ist möglich, in jeder Stufe (I, II, III, IV oder V) chirale/optisch aktive Zwischenstufen zu erhalten.
• 5) Es ist möglich, die unerwünschten Isomere zu razemisieren, um die Effizienz zu erhöhen und die Umweltbelastung zu vermindern.
• 6) Die obigen Faktoren tragen zur Verbesserung der Kostenwirksamkeit des hierin beschriebenen Verfahrens bei.

These preparation processes for the preparation of the compounds of general formula (I) as shown in Scheme 1 have the following advantages:

• 1) It requires fewer steps to prepare the compounds of formula (I).
• 2) Simple and readily available reagents / chemicals are used.
• 3) Milder reaction conditions are used in different steps.
• 4) It is possible to obtain chiral / optically active intermediates in each step (I, II, III, IV or V).
• 5) It is possible to racemize the undesired isomers to increase the efficiency and reduce the environmental impact.
• 6) The above factors contribute to the improvement of the cost effectiveness of the method described herein.

The Compounds of formulas (I), (II), (III) and (IV) can be with dissolve different methods to optically active compounds of the formulas (I), (II), (III) and (IV) to obtain clopidogrel of the desired stereochemistry (R.A. Sheldon, in Chirotechnology, Marcel Dekker, Inc. NY, Basel, 1993, 173-204 and references therein; A.N. Collins, G.N. Sheldrack and J.Crosby, in "Chirality in Industry II", John Wiley & Sons, Inc., 1997, 81-98 and references therein; E.L. Eliel and S.H. Wilen, in "Stereochemistry of Organic Compound ", John Wiley & Sons, Inc., 1999, 297-464 and references therein).

The method of dissolution comprises dissolving the racemic mixture (of formula I, II, III or IV) in a suitable solvent and adding a suitable chiral reagent. The medium may optionally contain about <5% water. The appropriate solvent is selected based on whether the diastereomeric salt is different. The separation of the diastereomeric salt can either result spontaneously or by addition of co-solvent or salting out or evaporation of the solvent or addition of an accompanying solvent. Alternatively, the separation can be done simply by stirring at one give appropriate temperature in solvent until one of the salts preferably precipitates. The purification of the diastereomeric salt is possible by refluxing in a suitable solvent. The free base is released from its salt using a suitable base reagent. The diastereomeric salt is dissolved or suspended in a mixture of water and organic solvent and neutralized with a base with stirring. The free base is obtained after separation of the aqueous layer and evaporation of the organic solvent.

The solvents used during the dissolution may contain solvents or mixtures thereof, such as (C ₁ -C ₄ ) -alcohol, (C ₁ -C ₄ ) -ketone, dimethylformamide, ethyl acetate, methyl acetate, methyl ethyl ketone, acetonitrile, propionitrile, THF, dioxanes and the same; The solvent used may optionally contain up to 5% water, but the presence of water or its amount is not important. The suitable temperature range for dissolution includes a temperature of 0 ° C to the reflux temperature of the solvent used, preferably 0 ° C to 80 ° C. The acidic chiral reagents that can be used to form a diastereomeric salt include tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, lactic acid, maleic acid, amino acids, and the like.

By repeated crystallization from a suitable solvent will that be precipitated Salt in the salt of the dextrorotatory isomer of the desired Diastereomers enriched to produce a product with constant optical To obtain rotation.

One suitable base reagent for the hydrolysis of diastereomeric salt includes sodium carbonate, potassium carbonate, Sodium bicarbonate and potassium bicarbonate in aqueous Medium at temperatures between 5 ° C and 25 ° C.

Finally, can the wished Salt of the compound of formula (II), (III) or (IV) or the pharmaceutical Acceptable salt of the compound of formula (I) from the corresponding Stereoisomer and a suitable acid are formed. The optical pure (S) - (+) - compound of formula (I) is 70% to 98% sulfuric acid in a suitable solvent converted into its bisulfate salt at a suitable temperature, to obtain (+) - clopidogrel bisulfate, polymorph I, as desired.

alternative can the formed diastereomers by conventional purification methods like crystallinating, column chromatography and the like, followed by cleavage of the salt, to a product of the desired To obtain stereochemistry. It is preferable to have such a chiral one To use agent that selectively a diastereomer with the R or S stereoisomer of intermediate I, II, III or IV can form. The used chiral reagent may be present in a molar ratio of 0.5 to 1.1.

The Determination of enantiomeric purity of (+) - dextrorotatory and (-) - levorotatory Enantiomers can be prepared by NMR proton spectroscopy with addition of a chiral reagent from rare earths (shift reagents) or by HPLC using a chiral stationary phase and by measurement the optical rotation performed become.

The absolute stereochemistry of the diastereomeric salt of the compounds II, III or IV leaves yourself with conventional Determine method, for example by X-ray crystallography. The absolute Stereochemistry of chiral compounds can also be determined by they are compared with reference standards known from the literature.

The pharmaceutically acceptable salts of mineral and organic acids optically active enantiomers of clopidogrel are used various acid salts produced, which are a part of this invention but not on hydrogen sulfates, hydrohalides, taurocholates and the like are.

In particular, the present process of the invention yields clopidogrel bisulfate having a melting point of 184 ± 3 ° C., which is characteristic of clopidogrel bisulfate Form I. Alternatively, clopidogrel bisulfate Form II can also be prepared by a known process (WO 99/65915, US Pat. FR 98 07464 ).

The process according to the invention also comprises the process of recycling the unwanted stereoisomer by racemization. The conditions for the racemization of all intermediates of the general formula II, III or IV and of the end product I comprise the same solvent and the same catalyst in equimolar amounts. Suitable catalysts are, in general, a base such as LDA (lithium diisopropylamide), KOH, NaOH, K ⁺ -tBuO ^-, NaOMe, NaH, KH and the like. Suitable solvents which during dissolution may include solvents or mixtures thereof, such as (C ₁ -C ₄ ) -alcohol, (C ₁ -C ₄ ) -ketone, ethyl acetate, methyl acetate, methyl ethyl ketone, THF, dioxane and the like; the solvent used may optionally contain up to 5% water. A suitable temperature range for dissolution comprises a temperature of 0 ° C to the reflux temperature of the solvent used, preferably 0 ° C to 80 ° C.

The in the present invention are described in the shown below.

EXAMPLE 1

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

To a solution of 8.98 g (86.33 mmol) of sodium bisulfite in water (27 ml) 12.4 g (86.33 mmol) of o-chlorobenzaldehyde are added, resulting in a white precipitate led. To the precipitate was added 15 g (0.107 mol) of 6,7-dihydro-4H-thieno [3,2-c] pyridine followed by the addition of 4.4 g (89.7 mmol) NaCN (dissolved in 15 ml of water). The reaction mixture was heated at 40-50 ° C for 6 hours and by pouring in Cooled water (50 ml). The mixture was 2 × 100 extracted with ethyl acetate. The organic layer was over anhydrous Dried sodium sulfate, and the solvent was reduced under reduced pressure Pressure removed. The yield of title product is 24 g (97%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR as follows:
IR spectrum (cm ^-1 ): 2227 (w, CN group)
Mass spectrum (m / z): 289.1 (M + H) ^+
13 C-NMR _(CDCl3): δ 136.46, 132.78, 132.38, 130.69, 130.46, 130.38, 129.90, 126.73, 124.96, 123.01, 115.09, 59.12, 49.30, 47.66, 25.47.
¹ H-NMR _(CDCl3): δ 7.2-7.7 (4H, m); 7.0 (1H, d), 6.69 (1H, d), 5.32 (1H, s), 3.78 (1H, d), 3.65 (1H, d); 2.8-δ3.0 (4H, m).

EXAMPLE 2

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

140.5 g (1 mol) of o-chlorobenzaldehyde and 65 g (1.01 mol) of KCN became 3.5 l given methanol. The reaction mixture was 139.05 g (1 mol) 6,7-dihydro-4H-thieno [3,2-c] pyridine and 190 ml of glacial acetic acid and heated for 20 hrs. At 60 ° C with stirring. After 8 hours began a precipitate appeared, and then the reaction mixture became poured into water and extracted with ethyl acetate (2 x 25 ml). The solvent was removed under reduced pressure and the residue as described in Example 1 cleaned. The product yield was 187 g (65%) with a melting point from 123-124 ° C.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 1.

EXAMPLE 3

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

27.6 g (266 mmol) of sodium bisulfite were dissolved in 100 ml of water, and There were 38.2 g (271 mmol) of o-chlorobenzaldehyde after dissolution in 100 ml of methanol. This resulted in a thick white slurry, the 1 hour at 60 ° C followed by the addition of 36.97 g (266 mmol) of 6,7-dihydro-4H-thieno [3,2-c] pyridine at 40 ° C, and was stirred for 2 hrs. To this reaction was carefully added 17.29 g (266 mmol) KCN dissolved in 50 ml of water, and the heating was continued for 5-6 hrs. At 40 ° C, what a white one Precipitation resulted. The reaction mixture was as in Example 1 described and the yield obtained was 54.6 g (72%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 1.

EXAMPLE 4

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

4.5 g (25.64 mmol) of 6,7-dihydro-4H-thieno [3,2-c] -5-pyridinium hydrochloride became (at 10 ° C) a solution of 1.95 g (30 mmol) of potassium cyanide in 2 ml of ice-cold water, followed by the dropwise addition of 5 ml of concentrated hydrochloric acid at 0 ° C. After the addition of HCl, 3.3 g (23.47 mmol) of o-chlorobenzaldehyde dissolved in 50 ml of methanol was added dropwise. Later, the reaction mixture was kept at room temperature for 3 days and then at 50 ° C for 3 hours. The pH was adjusted to 7.5-8.0 by the dropwise addition of NH ₄ OH and the product was extracted with ethyl acetate (2 x 50 mL). The solvent was dried over sodium sulfate and removed under reduced pressure. The amount of product obtained was 1.67 g (18%) with a melting point of 122-124 ° C.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 1.

EXAMPLE 5

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

6.25 g (44.46 mmol) of o-chlorobenzaldehyde was dissolved in 60 ml of toluene. The same Bottle of 10 ml of glacial acetic acid and 1.24 g (4.343 mmol) of cyclo [(S) -histidine (S) -phenylalanine] added, and the temperature was lowered to -25 ° C. This was followed by the encore of 7 g (50.35 mmol) of 6,7-dihydro-4H-thieno [3,2-c] pyridine, and the Reaction bottle was at -25 ° C for 6 hours rinsed with HCN gas (at a rate of 30 bubbles per minute) and then 2 days long at 31 ° C touched. The solvent was removed in vacuo, the residue was mentioned as in Example 1 cleaned. The amount of product obtained was 5.5 g (43%) with a Melting point of 124-125 ° C.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 1.

EXAMPLE 6

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

As described in Example 5, the adduct was prepared from 104.3 g (1 mol). Formed sodium bisulfite and 144.39 g (1.02 mol) of o-chlorobenzaldehyde, and it was at 31 ° C 150 g (1.078 mol) of 6,7-dihydro-4H-thieno [3,2-c] pyridine and stirred for 1 hour. It 102 g of TMS-CN were added dropwise and the temperature became 6 hours at 31 ° C held, resulting in a white Product led, which was isolated and purified by the method in Example 1. The yield obtained was 30 g (10%) with a melting point of about 123-124 ° C.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 1.

EXAMPLE 7

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

To 19.5 g (250 mmol) of KCN dissolved in water (20 ml) was added 43 g (250 mmol) of 6,7-dihydro-4H-thieno [3,2-c] pyridine, followed by the dropwise addition of 50 ml of concentrated hydrochloric acid. After completion of the addition, a solution of 33 g (230 mmol) of o-chlorobenzaldehyde in 100 ml of methanol was added dropwise and stirred at 31 ° C for 8 hours. The pH of the reaction mixture was adjusted to 7.5-8.0 with NH ₄ OH and the product was extracted with ethyl acetate (2 x 500 mL) and washed with water (2 x 500 mL), brine (500 mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain 50 g (74%) of product having a melting point of about 123-125 ° C.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 1.

EXAMPLE 8

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

To the solution 35.5 g (342 mmol) of sodium bisulfite in 35 ml of water became dropwise Added 49.1 g (349 mmol) of o-chlorobenzaldehyde, which immediately a solid adduct formed. To this was added 50 g (284.9 mmol) of 6,7-dihydro-4H-thieno [3,2-c] pyridine hydrochloride and refluxed for 5 hours. The usual Processing and purification gave 40 g (40%) of the product.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 1.

EXAMPLE 9

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

123.83 g (880 mmol) of o-chlorobenzaldehyde and 44 g (897 mmol) of sodium cyanide were added to 100 ml of a mixture of methanol and water (1: 1). To this was added 150 g (1070 mmol) of 6,7-dihydro-4H-thieno [3,2-c] pyridine followed by the addition of 10 ml of concentrated hydrochloric acid and stirring for 2 days at a temperature of 31 ° C. The pH of the reaction mixture was adjusted to 7.5-8.0 with NH ₄ OH and the product was extracted with ethyl acetate (2 x 50 ml) and washed with water (2 x 50 ml), brine (50 ml) , dried over sodium sulfate and isolated as described in Example 1. The amount of white solid product obtained was 33 g (13%), which was characterized as usual.

EXAMPLE 10

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

48 g (0.166 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile were suspended in 240 ml of t-BuOH and 18.26 g (0.332 mol) KOH in a batch with stirring added. The reaction mixture was refluxed at 80-82 ° C for 3 hours subjected, then at 30 ° C cooled, 240 ml of water were added and stirred for 20 minutes. The lower aqueous layer was separated and 720 ml freshly for 15 min chilled Water (5-10 ° C) added. The product was extracted with ethyl acetate (2 x 50 ml) and washed with Water (2 × 50 ml), brine (50 ml) and dried over sodium sulfate, followed by isolation by evaporation of the solvent under reduced pressure Print. After treatment with hexane, a solid was obtained. The Product yield was 48g (94%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR as follows:
IR spectrum (cm ^-1 ): 1656 (C = O group), 2333.7 (NH)
Mass spectrum (m / z): 307.2 (M + H) ^+
13 C-NMR _(CDCl3): δ 173.82, 135.32, 133.42, 133, 130.27, 129.99, 129.4, 126.98, 125.18, 122.98, 69, 12, 50, 77, 49, 10, 25, 82.
¹ H-NMR CDCl _3): δ 7.4-7.5 (4H, m), 7.24 (1H, d), 7.0 (1H, s), 6.66 (1H, d), 6 , 0 (1H, s), 4.88 (1H, d), 3.61 (2H, q), 2.88 (4H, m).
Melting point: 125-127 ° C.

EXAMPLE 11

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

100 mg (0.3466 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile of formula (IV) prepared according to Example 1-9 were dissolved in 5 ml HCl and 1 ml of trifluoroacetic acid solved, and 5 ml of t-butanol was added and refluxed for 4 hours subjected. Upon completion of the reaction, the product was as in Example 11 mentioned isolated. The product yield was 40 mg (38%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, and found to be identical to the product obtained in Example 10.

EXAMPLE 12

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

To 100 mg (0.346 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile of the formula (IV) prepared according to Example 1-9, 5 ml of formic acid and 5 ml of concentrated hydrochloric acid was added, and the reaction mixture was stirred for 48 hours at 25-30 ° C and subsequently at about 100 ° C 6 For hours a reflux process and stirred at 25-30 ° C for 8 days. After completion of the reaction The reaction mixture was treated as mentioned in Example 10. The product yield was 50 mg (47%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, and found to be identical to the product obtained in Example 10.

EXAMPLE 13

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

200 mg (0.694 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile of the formula (IV), prepared according to Example 1 -9, were added to 5 ml of HBr and 5 ml of H ₂ O and stirred at room temperature for 72 hours. The reaction mixture was refluxed at 100 ° C for 11 hours, and the product was isolated as mentioned in Example 10. The product yield was 50 mg (47%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, and found to be identical to the product obtained in Example 10.

EXAMPLE 14

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

1 g (3.47 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile was dissolved in 5 ml H ₂ SO ₄ (50%) solved. To the reaction mixture was added 0.405 g of anhydrous NaCl and the reaction was refluxed for 2-3 h. At the end of the reaction, the product was isolated as described in Example 10. The product yield was 600 mg (57%).

The product was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 10.

EXAMPLE 15

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

1 g (3.47 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile was dissolved in 5 g (5 mmol). HClO ₄ , and 10 ml of H ₂ O were added to the reaction mixture. The reaction mixture was refluxed at 105 ° C for 7 hours and then stirred at room temperature for 12 hours. The pH was raised to 10-12 with a 10% (w / v) NaOH solution and then extracted with 50 ml of dichloromethane. The organic layer was isolated and washed with water and evaporated under reduced pressure. The residue was treated with hexane to give 50 mg (47%) of solid having a melting point of 125-127 ° C.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, and found to be identical to the product obtained in Example 10.

EXAMPLE 16

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

1 g (3.47 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile was dissolved in 10 ml of t-BuOH and 277 mg (6.925 mmol) of crushed NaOH were added with stirring all at once ben. The reaction mixture was refluxed for 4 hrs at 80-82 ° C and then cooled to room temperature. The product was isolated by extraction with ethyl acetate. The organic extract was evaporated and oily material left after treatment with hexane gave 400 mg of solid (38%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, and found to be identical to the product obtained in Example 10.

EXAMPLE 17

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

3 g (0.01 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile were dissolved in 50 ml of acetone. To this solution was added 1 g (0.023 mol) of NaOH dissolved in 10 ml of water, followed by 5 ml of H ₂ O ₂ (0.05 mol, 30% (w / v)) in a batch and Solution was refluxed for 3 hours. The reaction mixture was cooled to room temperature and a further 5 ml of H ₂ O ₂ (0.05 mol, 30% (w / v)) added and stirred for 12 hours. The product was isolated by the addition of excess water and extracted with 1 L of ethyl acetate. The organic extract was evaporated to obtain 2.8 g of oily crude material which after hexane treatment gave 1 g of solid (31%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, and found to be identical to the product obtained in Example 10.

EXAMPLE 18

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

To 10 g (0.0346 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile, dissolved in 30 ml of isopropyl alcohol, was slowly added 3.9 g (0.0589 mol) of crushed KOH (85%) and the mixture was heated and 120 ml of water added. The pH of the aqueous Layer became more diluted hydrochloric acid brought to 7. The White solid precipitate was filtered and washed with 100 ml of water. The product yield was 9 g (85%) with a melting point of 122 ° C.

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, and found to be identical to the product obtained in Example 10.

EXAMPLE 19

(±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamidhydrogensulfatsalz (II)

2 g (6.48 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide of the formula (IV) were dissolved in 10 ml Acetone dissolved. To the reaction mixture was added 1 ml of sulfuric acid, and the mixture was stirred for 0.5 hr. Then, 5 ml of diethyl ether was added and stirred overnight at room temperature to obtain a salt. The salt (2 g, 76%) was isolated by filtration and washed with acetone.
Melting point: 199.1 ° C
IR spectrum: 1682.8, 3116 (cm ^-1).

EXAMPLE 20

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetic acid (III)

100 mg (0.3466 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile were dissolved in 2 ml of t-butanol, and 1.5 ml of HCl was added. The reaction mixture became 9 Hours at 100 ° C a reflux process subjected. After completion of the reaction, water was added and the pH was brought to 4 with 10% KOH solution. The product was extracted with 5 ml of dichloromethane, and hereinafter was added proceed in the previous example. The yield was 40 mg (38%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR as follows:
IR spectrum (cm ^-1 ): 1637.5 (s, C = O group), 3399.3 (OH)
Mass peaks (m / z): 308.1 (M + H) ^+
1 H-NMR (δ ppm): δ 7.22-7.89 (4H, m), δ 7.11-7.12 (1H, d), δ 6.61-6.63 (1H, d) , δ 3.57-3.67, (2H, d), δ 4.13 (2H, s), δ 3.32-3.42 (2H, s).

EXAMPLE 21

(±) - (2-Chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetic acid (III)

5 g (17.33 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile were added to 100 ml of HCl, and the mixture was stirred for 2 days and subsequently 15 hours of a reflux process subjected. At the end, the reaction mixture was poured into water, and the pH was raised to 4 with 10% KOH. The product was labeled 2 Extracted dichloromethane, washed with water, and the organic Layer was evaporated to obtain the residue.

The usual cleaning of the residue gave 2 g of solid (38%).

The product obtained was characterized using an IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR and found to be identical to the product obtained in Example 20.

EXAMPLE 22

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

10 g (32.62 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide (prepared according to Example 15) are mixed with 19.8 g (161.7 mmol) of DMFDMA (Dimethylformamiddimethylacetal) mixed in 100 ml of methanol. The Mixture was refluxed at 70 ° C for 14 hours. Subsequently The reaction mixture was cooled in water and extracted with ethyl acetate. The organic extract was evaporated under reduced pressure, by 5 g (48%) of an oily To get product. This oil was used without further treatment to salts of ester (I) manufacture.

EXAMPLE 23

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

15 g (0.0490 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide was dissolved in 105 ml of methanol with stirring , To the above solution, 45 ml (0.823 mol) of concentrated sulfuric acid (98%) was added dropwise at room temperature over a period of 1.5 hours. Subsequently, the mixture was refluxed at 80 ° C for 26 hours, followed by distillation of methanol. To the remaining residue was added with stirring 200 ml of ethyl acetate at a temperature between 0 ° C and 5 ° C. Thereafter, 99 g (1.764 mol) of KOH dissolved in 300 ml of water was added to the reaction, and the reaction was stirred for 0.5 hr. Finally, the reaction mixture was filtered and allowed to stand. The organic layer was isolated and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated to obtain an oily product. The yield was 10 g (64%).

EXAMPLE 24

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetathydrogensulfatsalz (I)

10 g Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate according to Example 22, were dissolved in 100 ml of ice-cold acetone, and 2 ml of concentrated sulfuric acid were added at 0 ° C to 5 ° C. The formed crystalline white until cream-colored product was isolated by filtration and with Washed 20 ml of acetone. The product obtained was in a vacuum oven at 50 ° C dried. The yield of the title product was 7.2 g (56%).

EXAMPLE 25

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

2 g (0.00652 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide and 2 ml (0.0308 mol) of methanesulfonic acid and 20 ml of methanol were mixed and the solution was refluxed for 12 hours at 85 ° C. The excess solvent was removed under reduced pressure. The pH was adjusted to about 9 with an aqueous solution of sodium bicarbonate at 0 ° C and the product was extracted with 70 ml of ethyl acetate. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by column chromatography with hexane: ethyl acetate as eluent. The resulting product was concentrated, stored under nitrogen and stored in the refrigerator before being converted to a salt. The yield of title product was 0.419 g (20%).

EXAMPLE 26

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

1 g (0.00326 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide was dissolved in 20 ml of methanol and added 85 ° C subjected to a reflux process. During the reflux, 10 ml of polyphosphoric acid was added dropwise over a period of 1 hour, and the reflux process was continued for a further 6 hours. Excess solvent was removed under reduced pressure. To the residue was added 50 ml of ethyl acetate at 0 ° C and the reaction mixture was brought to pH 9 with aqueous NaHCO ₃ or made basic. From the two separate phases, the organic layer was isolated, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by column chromatography with hexane: ethyl acetate (9: 1) as eluent. The resulting product was stored under nitrogen and stored in the refrigerator before being converted to a salt. The yield of title product was 310 mg (30%).

EXAMPLE 27

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

1 g (0.00326 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide was added to 2 ml at 0 ° C Toluene, followed by the dropwise addition of 1 ml of titanium tetrachloride, and the reaction was stirred at 0 ° C for 1 hour. Then, 18 ml of methanol was added, and the reaction was stirred at 29 ° C for 36 hours and then refluxed for 3 hours. The solvent was distilled under reduced pressure and the residue was added to aqueous sodium carbonate at 0 ° C. The product was extracted with 20 ml of ethyl acetate and the organic layer was isolated, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by column chromatography with hexane: ethyl acetate as eluent. The resulting product was stored under nitrogen and stored in the refrigerator before being converted to a salt. The yield of title product was 0.157 g (12-15%).

EXAMPLE 28

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

To 5 g (16.31 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide was added 25 ml of POCl ₃ with stirring given. The contents were refluxed until the amide was completely consumed (about 4 hours). Thereafter, 20 ml of methanol and 5 ml of concentrated H ₂ SO _{4 were} added and stirred at room temperature for 1 hour. Later, the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled with aqueous Na ₂ CO ₃ at 0 ° C and extracted with 200 ml of ethyl acetate. The organic layer was isolated, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by column chromatography with hexane: ethyl acetate as eluent. The resulting product was stored under nitrogen and stored in the refrigerator before being converted to a salt. The yield of title product was 0.943 g (18%).

EXAMPLE 29

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

1 g (0.00326 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide was dissolved in 10 ml of methanol. The reaction mixture was saturated with HCl (g) at 0 ° C, stirred at room temperature for 4 hours, and then refluxed for 6 hours. The solvent was removed under reduced pressure. To the residue was added 10 ml of ethyl acetate and aqueous NaHCO ₃ until the pH is 9 (0 ° C). The organic layer was isolated, dried over anhydrous Na ₂ SO ₄ , evaporated under reduced pressure. The residue was further purified by column chromatography with hexane: ethyl acetate as eluent. The resulting product was stored under nitrogen and stored in the refrigerator before being converted to a salt. The yield of title product was 0.188 g (18%).

EXAMPLE 30

(±) -Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

To 1 g (0.00326 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide was added 3 g (24.2 mmol) of DMFDMA (dimethylformamide dimethyl acetal) and 10 ml of methanol. The reaction mixture was refluxed at 70 ° C for 14 hours, then poured into water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , evaporated under reduced pressure. The residue was further purified by column chromatography with hexane: ethyl acetate (9: 1) as eluent. The yield of title product was 500 mg (48%).

EXAMPLE 31

(S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetatamid (II)

• a) A solution with 5 g (16.31 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (mfd as explained in Example 10-15) and 4.15 g (16.2 mmol) of (15) (+) - camphor-10-sulfonic acid monohydrate in 100 ml of acetone was stirred for 20 hours at room temperature. Subsequently was stored in a freezer for 1 week. It formed some crystals. The volume was removed by evaporation of solvent concentrated under reduced pressure, and recrystallization in a freezer for A few days gave 3.3 g (yield: 75%) of (S) -2- (2-chlorophenyl) - (4,5,6,7-tetrahydrothieno [3,2-c] pyrid-5-yl) -acetamide (+) - camphorsulfonic acid salt. The salt was further purified by recrystallization in acetone, until a constant specific optical rotation was obtained.

• b) 3,3 g (S)-(+)-(2-Chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetatamid-10-D-camphersulfonsäuresalz wurden zu 20 ml gesättigter wässriger Na₂CO₃-Lösung gegeben, und das Produkt wurde mit 20 ml Ethylacetat extrahiert. Die organische Schicht wurde isoliert, über Na₂SO₄ getrocknet und unter reduziertem Druck eingeengt. Das erhaltene Produkt war ein Rohöl, das nach Reinigung 1,6 g an weißen Kristallen ergab (64%).

The product obtained was suitably dried. The typical physicochemical characteristics of the product obtained are as follows:
Melting range: 223-225 ° C (dec.)
SOR: + 51 ° C (C = 1, MeOH)

• b) 3.3 g of (S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide-10-D-camphorsulfonic acid salt were added to 20 ml of saturated aqueous Na ₂ CO ₃ solution, and the product was extracted with 20 ml of ethyl acetate. The organic layer was isolated, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product obtained was a crude oil which after purification yielded 1.6 g of white crystals (64%).

The product obtained was characterized by various physico-chemical properties, including IR spectrum, mass spectrum, ¹³ C-NMR and ¹ H-NMR, which are listed below:
Melting point: 153-154 ° C
SOR: + 41 ° C (C = 1, MeOH)
Optical purity: 99.5 by chiral HPLC column
IR spectrum (cm ^-1 ): 1656 (s, C = O group), 2333.7 (m, CN), 3357.9 (s, NH str)
Mass peaks (m / z): 307.2 (M + H) ^+
13 C-NMR _(CDCl3): δ 173.25, 134.84, 132.87, 132.65, 129.98, 129.56, 129.0, 126.72, 124.87, 122.64, 68.65, 50.43, 48.73, 25.28
¹ H-NMR _(CDCl3): δ 7.4-7.5 (4H, m), 7.07 (1H, d), 7.06 (1H, d), 6.66 (1H, d), 6.5 (1H, s), 4.9 (1H, s), 3.6 (2H, q), 2.88 (4H, m).
HPLC purity: 99.85%.

EXAMPLE 32

(S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetatamid (II)

• a) 2 g (6.5 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide was added to 30 ml of acetone , To the above solution, 0.82 g (3.28 mmol) of (1S) - (+) - camphor-10-sulfonic acid monohydrate in 10 ml of acetone was added over 4 hours at 15-20 ° C. The reaction mixture was for stirred for a further 5 min, with some crystals formed. The solvent was distilled under reduced pressure, and then the reaction mixture was kept at a temperature below 8 ° C in a cold state. The precipitate formed was filtered and washed with solvent. The yield of title product was 1.2 g (60%) with a melting temperature in the range of 223-225 ° C and [α] _D = + 51 ° (C = 1, CH ₃ OH).
• b) To the suspension of 1.1 g of (+) - (S) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide- ( 1S) - (+) - camphor-10-sulfonic acid salt in 50 ml of water was added 50 ml of saturated Na ₂ CO ₃ solution in water. The reaction mixture was stirred for a while, followed by the addition of 100 ml of ethyl acetate. The organic layer was isolated and distilled to obtain the title product. The amount of product obtained was 600 mg (60% based on the dextro isomer present in the racemic mixture).

The product obtained was characterized by various physicochemical properties listed below;
Melting range: 149-153 ° C
[α] _D : + 38 ° (C = 1, CH ₃ OH) with% ee = 97.24%.

EXAMPLE 33

(S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetatamid (II)

• a) 5 g (16.3 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide was added to 60 ml of ethyl acetate. 2 g (8.6 mmol) of (1S) - (+) - camphor-10-sulfonic acid monohydrate were dissolved in a minimum amount of water and the above solution in a batch and stirred at 35-40 ° C for 1 hour. In a short time formed a salt and was isolated, with 50 ml Washed acetone and dried. The amount of product received was 1.81 g (36%).

• b) Zu der Suspension von 1,8 g (S)-(+)-(2-Chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamid-(1S)-(+)-campher-10-sulfonsäuresalz in 100 ml Wasser wurden 50 ml Natriumbicarbonatlösung in Wasser gegeben. Nach dem Rühren des Gemisches wurden 150 ml Ethylacetat zugegeben. Die kombinierten organischen Schichten wurden abdestilliert, um das Titelprodukt zu erhalten. Die erhaltene Produktmenge war 1 g (56%).

The product obtained was characterized by various physicochemical properties listed below;
Melting range: 223-225 ° C
[α] _D : + 52.12 ° (C = 1, CH ₃ OH).

• b) To the suspension of 1.8 g of (S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide- ( 1S) - (+) - camphor-10-sulfonic acid salt in 100 ml of water was added 50 ml of sodium bicarbonate solution in water. After stirring the mixture, 150 ml of ethyl acetate was added. The combined organic layers were distilled off to obtain the title product. The amount of product obtained was 1 g (56%).

The product obtained was characterized by various physico-chemical properties similar to those of Example 31 and listed below;
Melting range: 153-154 ° C
[α] _D : + 42 ° (C = 1, CH ₃ OH) and with% ee = 100% (by chiral HPLC column chromatography).

EXAMPLE 34

(R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetatamid (II)

• a) 5 g of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide (I) (0.016 mol) was added to 60 ml of ethyl acetate, and added to the solution 2 g (0.0086 mol) of (1R) - (-) - camphor-10-sulfonic acid monohydrate were obtained in one batch in 5 ml of water. The reaction mixture was at ambient temperature Stirred for 1 hour. Later The reaction mixture was kept in a freezer for 1 week stored, with some crystals were seen. After evaporation of the solvent at reduced pressure and stored in the cold state that fell Salt off, then filtered and washed with 50 ml of acetone. The amount of product obtained was 1.7 g (39%).

• b) Zu der Suspension von 1,6 g (R)-(–)-(2-Chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamid-(1R)-(-)-campher-10-sulfonsäuresalz in 100 ml Wasser wurden 50 ml Natriumbicarbonatlösung in Wasser gegeben. Nach dem Rühren des Gemisches wurden 150 ml Ethylacetat zugegeben. Die organische Schicht wurde extrahiert, und die kombinierte organische Schicht wurde abdestilliert, um das Titelprodukt zu erhalten. Die erhaltene Produktmenge war 900 mg (36%).

The product obtained was of various physico-chemical properties of (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide and its (-) - CSA salt, both of which are listed below;
Melting range (-) - CSA - (-) acetamide: 219-220 ° C
[α] _D (-) - CSA - (-) acetamide: -52.12 ° (C = 1, CH ₃ OH).

• b) To the suspension of 1.6 g of (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetone Mid (1R) - (-) - camphor-10-sulfonic acid salt in 100 ml of water was added 50 ml of sodium bicarbonate solution in water. After stirring the mixture, 150 ml of ethyl acetate was added. The organic layer was extracted, and the combined organic layer was distilled off to obtain the title product. The amount of product obtained was 900 mg (36%).

The product obtained was characterized by various physicochemical properties listed below;
Melting range: 145-149 ° C
[α] _D Acetamide: -36.49 ° (C = 1, CH ₃ OH).

EXAMPLE 35

(S) - (+) - Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetatbisulfat (I)

15 g (+) - (S) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide (0.0489 mol) were converted into corresponding esters, as in Example 23 explained. The ester leaves as explained in Example 24 Turn process into its hydrogen sulfate salt. The amount of product obtained was 7 g (44.5%) with a melting point of 184-185 ° C.

Melting point, IR spectrum and XRD of the product obtained are similar to those of in EP 281459 and US 4847265 It is now referred to as Form I polymorph of clopidogrel bisulfate (WO 99/65915).

The product obtained was characterized by various physicochemical properties listed below;
[α] _D : + 55 ° (C = 1, CH ₃ OH).
Melting point: 185 ° C ± 2 ° C
IR spectrum: 2980, 1755, 1224, 1175 and 840, respectively, with the corresponding percent transmission of about: 45; 16; 19; 15; 45th

It showed that XRD corresponded to Form I, XRD, indicated in WO 99/65915.

EXAMPLE 36

(R) - (-) - Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetatbisulfat (I)

Under Using 5 g, the (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide obtained in Example 34 above as explained in Example 23 be transformed into an ester. Subsequently, the ester as in Example 24 are converted into hydrogen sulfate salt. The obtained Product amount was 3.01 g (44%).

The product obtained was characterized by various physicochemical properties listed below; [α] _D : -52 ° (C = 1, CH ₃ OH).

EXAMPLE 37

(S) - (+) - Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetatbisulfat (I)

• a) 10 g (0.0185 mol) of (1S) - (+) - camphor-10-sulfonic acid salt of (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,7-c ] pyrid-5-yl) acetamide were dissolved in 40 ml of methanol at 0 ° C. To the solution was added 15 ml (0.28 mol) of concentrated H ₂ SO ₄ dropwise over 1.5 hrs. The reaction temperature was gradually raised, and the reaction was refluxed for 26 hours. At the end, the solvent was distilled off under reduced pressure. The remaining residue was mixed with 120 ml of ethyl acetate and the pH was adjusted to between 9 and 10 with aqueous sodium carbonate for extraction. The organic layer was isolated, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The product obtained was purified by column chromatography using hexane: ethyl acetate (9: 1) as eluent. The combined eluent was evaporated under reduced pressure to obtain 5.76 g (97%) of product.
• b) 2 g of (S) - (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate were prepared according to the procedure described in Example 24 described method transformed into bisulfate salt. The amount of product obtained was 2.2 g (84%), which was found to be identical to the product obtained in Example 35.

EXAMPLE 38

Polymorph I of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate bisulfate salt (I)

52.5 ml of ice-cold acetone were added to 17.5 g of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5) with stirring at 0 ° C -yl) acetate. 3.6 ml of concentrated H ² SO ^{4 were} added dropwise and the temperature was kept below 5 ° C. Further, 20 ml of acetone was added, and the reaction mixture was further stirred for 4 hours at room temperature. The precipitate was isolated (17 g, 74%), dried under vacuum at temperatures not exceeding 50 ° C.

The resulting product was characterized by various physico-chemical properties and was found to be identical to the product obtained in Example 35, as shown below:
Specific optical rotation: + 54 ° (C = 1, CH ₃ OH).
Melting point: 185 ° C ± 2 ° C
IR and XRD corresponded to the data reported in the literature.

EXAMPLE 39

Polymorph I of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate bisulfate salt (I)

To 2.1 g of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate was added 7.6 ml of acetone to obtain to get a clear solution. To this solution was added slowly 0.887 g of H ₂ SO ₄ (80%) and the temperature was maintained at about 20 ° C under nitrogen. Later, the reaction mixture was cooled to -20 ° C for 2 hours, and then the temperature was brought to room temperature (20 ° C). The reaction mixture was stirred at 20-25 ° C. The precipitate was isolated (600 mg), dried in vacuo at a temperature not exceeding 50 ° C.

The resulting product was characterized by various physico-chemical properties and was found to be identical to the product obtained in Example 35, as shown below:
SOR (α ^D ): + 54.03 ° (C = 1.89, MeOH).
Melting point: 185 ° C ± 1 ° C
Chiral purity: 99.63% (ee)
IR and XRD corresponded to the data reported in the literature.

EXAMPLE 40

Polymorph I of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate bisulfate salt (I)

To 2 g of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate was added 5 ml of acetone and 25-30 ° C stirred. The temperature of the reaction mixture was raised from 25 ° C to 65 ° C and then maintained at 65 ° C for 5 min. At a temperature of 50-52 ° C, 0.676 g of concentrated H ₂ SO _{4 was} added. The reaction mixture was cooled from 52 ° C to 5 ° C and additional acetone was added and stirred for 5 min. Later, the reaction mixture was stirred for 12 hours at 25-30 ° C, the resulting thick precipitate was filtered, washed with 5 ml of acetone and the residue was dried in a vacuum oven. The yield of title product was 1.27 g (47%).

The resulting product was characterized by various physico-chemical properties and was found to be identical to the product obtained in Example 35, as shown below:
SOR (α ^D ): + 54.03 ° (C = 1.89, MeOH).
Melting point: 185 ° C ± 1 ° C
Chiral purity: 99.80% (ee)
IR and XRD corresponded to the data reported in the literature.

EXAMPLE 41

Polymorph I of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate bisulfate salt (I)

To 1.98 g of (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate was added 5 ml of ace Clay and stirred at 25-30 ° C. The temperature of the reaction mixture was raised from 25 ° C to 50-52 ° C, and 0.7 g of concentrated H ₂ SO ₄ (95%) was added in one batch with constant stirring, and the reaction mixture suddenly rose for 10 min 0 ° C to -5 ° C cooled. Later, the reaction mixture was stirred for 12 hours at 25-30 ° C, the resulting thick precipitate was filtered, washed with 5 ml of acetone, and the residue (1.6 g, 62%) was dried in a vacuum oven.

The resulting product was characterized by various physico-chemical properties and was found to be identical to the product obtained in Example 35, as shown below:
SOR (α ^D ): + 55.96 ° (C = 1.89, MeOH).
Melting point: 185 ° C ± 1 ° C
Chiral purity: 99.85% (ee)
IR and XRD corresponded to the data reported in the literature.

EXAMPLE 42

Racemization of (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide (II)

20 g of a mixture of levorotatory (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide of the formula (II) and 11 g of potassium t-butoxide in 100 ml of t-butanol were added for 30 min long at 25 ° C up to 30 ° C touched. After completion of the reaction, the reaction mixture was poured into 750 ml poured cold water to get a yellow precipitate. This resulting solid was filtered and dissolved in methylene dichloride. The organic layer was 2 × 100 ml DM water (2 x 100 ml) washed and concentrated to 18 g of the corresponding racemic To get amides, d. H. (±) -2- (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II).

The specific optical rotation of the racemic amide (II) was ± 1 ° (C = 1, CH ₃ OH).

EXAMPLE 43

Racemization of (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide (II)

1 g. levorotatory (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide of formula (II) and 1 g of potassium t-butoxide in 20 ml of DMSO became 3 For hours at 50 ° C up to 60 ° C touched. After completion of the reaction, the reaction mixture was dissolved in 150 ml poured cold water to get a yellow precipitate. This resulting solid was filtered and methylene dichloride solved. The organic layer was washed with 2 x 25 ml DM water (2 x 25 ml). washed and concentrated to 0.8 g of the corresponding racemic To get amides, d. H. (±) -2- (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II).

The specific optical rotation of the racemic amide (II) was ± 0.5 ° (C = 1, CH ₃ OH).

EXAMPLE 44

Racemization of (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide (II)

1 g of a mixture of levorotatory (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide of the formula (II) and 250 mg of sodium hydride in dry tetrahydrofuran 3 hours at 25 ° C up to 30 ° C touched. After completion of the reaction, the reaction mixture became slowly in Poured 150 ml of cold water to give a yellow precipitate. This resulting solid was filtered and methylene dichloride solved. The organic layer was washed with 2 x 25 ml DM water (2 x 25 ml). washed and concentrated to 0.95 g of the corresponding racemic To get amides, d. H. (±) -2- (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II).

EXAMPLE 45

Racemization of (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide (II)

1 g of a mixture of levorotatory (R) - (-) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide of the formula (II) and 21 g of potassium t-butoxide in 100 ml of DMSO was stirred at 50 ° C to 60 ° C for 3 hours. After completion of the reaction, the reaction mixture was poured into 750 ml of cold water to get a yellow precipitate. This resulting solid was filtered and dissolved in methylene dichloride. The organic layer was washed with 2 x 100 ml DM water (2 x 100 ml) and concentrated to give 0.8 g of the corresponding racemic amide, ie (±) - (2-chlorophenyl) - (6,7-). dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide.

EXAMPLE 46

(S) - (+) - Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

5 g of (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide were dissolved in 35 ml of methanol and the solution was brought to 0 to Cooled to -5 ° C. 15 ml (0.28 mol) of concentrated H ₂ SO ₄ (98%) were added slowly over 1 hour keeping the temperature at -5 ° C. After completion of the addition, the reaction mixture was mixed at room temperature for 30 minutes. The solution was subjected to a reflux reaction at 60 ° C for 36 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was added to 200 ml of chilled water and cooled to -5 ° C. The pH of the reaction mixture was adjusted to between 9 and 10 with aqueous sodium carbonate. The residue was extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The combined eluent was evaporated under reduced pressure to obtain 3.2 g of a purified product, which was purified by column chromatography using hexane: ethyl acetate (9: 1) as eluent.

EXAMPLE 47

(S) - (+) - Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

5 g of (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide was dissolved in 45 ml of methanol, followed by 15 ml of toluene. Immediately, 5 ml (0.28 mol) of concentrated H ₂ SO _{4 was} added and then another 10 ml of concentrated H ₂ SO ₄ were slowly added while the temperature was maintained at 90 ° C. Thereafter, the reaction mixture was subjected to a reflux reaction at 90 ° C for 13 hours. The solvent was distilled off under reduced pressure. To the residue was added 50 ml of water, and the pH of the reaction mixture was adjusted to between 9 and 10 with aqueous sodium carbonate. The residue was extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The combined eluent was evaporated under reduced pressure to give 2.8 g of crude product, which was purified by column chromatography using hexane: ethyl acetate (9: 1) as eluent.

EXAMPLE 48

(S) - (+) - Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

5 g of (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide were dissolved in 50 ml of methanol and the solution was brought to -15 Cooled ° C. 15 ml (0.28 mol) of concentrated H ₂ SO ₄ (98%) were added dropwise over 1 hour, keeping the temperature at -15 ° C. After completion of the addition, the reaction mixture was gradually raised and stirred at 31 ° C for 30 minutes, and then subjected to a reflux reaction at 70 ° C for 21 hours. The solvent was distilled off under reduced pressure, and to the residue were added 50 ml of water and stirred for 30 minutes, followed by cooling to -5 ° C. The pH of the reaction mixture was adjusted to between 9 and 10 with aqueous sodium carbonate. The residue was extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The yield was 3.8 g of crude product which had been purified by column chromatography using hexane: ethyl acetate (9: 1) as eluent.

EXAMPLE 49

(S) - (+) - Methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

5 g of (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide were dissolved in 20 ml of methanol and the solution was brought to 65 ° C heated to 70 ° C. 15 mL (0.28 mol) of cooled concentrated H ₂ SO ₄ (98%) was added slowly over 1 hour, keeping the temperature at -15 ° C. After completion of the addition, the reaction mixture was heated at 70 ° C for 16 hours. The solvent was distilled off under reduced pressure, and to the residue were added 50 ml of water and stirred for 30 minutes, followed by cooling to -5 ° C. The pH of the reaction mixture was adjusted to between 9 and 10 with aqueous sodium carbonate. The residue was extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The combined eluent was evaporated under reduced pressure to give 2.8 g of crude product, which was purified by column chromatography using hexane: ethyl acetate (9: 1) as eluent to give 2 g of the title compound (I) and 1 g of starting material (S. ) - (+) - (II).

EXAMPLE 50

(S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (II)

• a) A solution of 5 g (16.31 mmol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide (mfd as in Examples 10-15) and 4.15 g (16.2 mmol) of (1S) - (+) - camphor-10-sulfonic acid monohydrate in 100 ml of acetone was kept warm for 20 hours and then at stored at a temperature below 10 ° C. Some crystals appeared; the mother liquor was further concentrated and the recrystallization is repeated, followed by storage under cold conditions for a few days, giving 3.1 g (yield 70%) of (S) -2- (2-chlorophenyl) - (4,5,6,7-tetrahydrothieno [3,2-c] pyrid-5-yl) -acetamide (+) - camphorsulfonic acid salt revealed. The salt was further purified by recrystallization in acetone, until a constant specific optical rotation was obtained.

• b) 3,1 g (S)-(+)-(2-Chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamid-10-D-camphersulfonsäuresalz wurden zu 20 ml gesättigter Na₂CO₃-Lösung gegeben, und das Produkt wurde mit 20 ml Ethylacetat extrahiert. Die organische Schicht wurde isoliert, über Na₂SO₄ getrocknet und unter reduziertem Druck konzentriert. Das erhaltene Produkt war ein Rohöl, das nach Reinigung 1,5 g weiße Kristalle (60%) ergab.

The product obtained was suitably dried. The typical physico-chemical properties of the product obtained are as follows:
Melting range: 223-225 ° C (dec.)
SOR: + 52 ° (C = 1, MeOH)

• b) 3.1 g of (S) - (+) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide-10-D-camphorsulfonic acid salt were added to 20 ml of saturated Na ₂ CO ₃ solution, and the product was extracted with 20 ml of ethyl acetate. The organic layer was isolated, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product obtained was a crude oil which after purification gave 1.5 g of white crystals (60%).

EXAMPLE 51

chiral Removal of the (-) stereoisomer from a mixture that has a surplus on (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate

2 g (0.0173 mol) of methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (with ee of 80%) were dissolved in 10 ml of acetone was dissolved, and the reaction mixture was stirred for 20 min, followed by reflux. To the reaction mixture was added 1.49 g of (1S) - (+) - camphor-10-sulfonic acid hydrate in 0.8 ml of water, followed by 1 ml of acetone. The entire reaction mixture was then refluxed for 1 hour and gradually cooled. It was then stirred overnight at room temperature. The clear solution was further cooled to 0 ° C to -5 ° C to give a precipitate. The resulting salt was added to ethyl acetate and water, which was later basified with NaHCO ₃ , the organic layer was washed with water, concentrated under reduced pressure to give 0.386 g of free base with a chiral purity = 99.85 (+) - isomer (ee = 99.7%).

EXAMPLE 52

chiral Removal of the (-) stereoisomer from a mixture that has a surplus on (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate

2 g (0.0173 mol) of methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (with ee of 90 °) were dissolved in 10 ml of acetone, and the reaction mixture was stirred for 10 min, followed by reflux. To the reaction mixture was added 1.49 g of (1S) - (+) - camphor-10-sulfonic acid hydrate in 0.8 ml of water, followed by 1 ml of acetone. The entire reaction mixture was then refluxed for 1 hour and gradually cooled. It was then stirred overnight at room temperature. The clear solution was further cooled to 0 ° C to -5 ° C to give a precipitate. The resulting salt was added to ethyl acetate and water, which was later basified with NaHCO ₃ , the organic layer was washed with water, concentrated under reduced pressure to give 0.386 g of free base with a chiral purity = 99.85% (+) - isomer ( ee = 99.70.

EXAMPLE 53

chiral Removal of the (-) stereoisomer from a mixture that has a surplus on (+) - methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

2 g (0.0173 mol) of methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (with ee of 95%) were dissolved in 10 ml of acetone, and the reaction mixture was stirred for 10 min, followed by reflux. To the reaction mixture was added 1.49 g of (1S) - (+) - camphor-10-sulfonic acid hydrate in 0.8 ml of water, followed by 1 ml of acetone. The entire reaction mixture was then refluxed for 1 hour and gradually cooled. It was then stirred overnight at room temperature. The clear solution was further cooled to 0 ° C to -5 ° C to give a precipitate. The resulting salt was added to ethyl acetate and water, which was later basified with NaHCO ₃ , the organic layer was washed with water, concentrated under reduced pressure to give 0.386 g of free base with a chiral purity = 99.85% (+) - isomer ( ee = 99.7%).

EXAMPLE 54

Dissolve (±) -methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate (I)

33 g (0.1 mol) of (±) -methyl (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetate were dissolved in 200 ml of acetone, and the reaction mixture was heated to 60 ° C to 70 ° C, followed by reflux for 15 minutes. To the reaction mixture was added 25.6 g of (1S) - (+) - camphor-10-sulfonic acid hydrate, solved in water, with the formation of salt beginning at 60 ° C to 70 ° C. After completion of the salt formation, the reaction mixture gradually became Room temperature and then to 0 ° C up to 5 ° C cooled. The diastereomeric salt was isolated by filtration with acetone washed and dried. The yield of diastereomeric product was 20.5 g (70%).

The Preparation of the (-) isomer the title compound was carried out using dilute sodium bicarbonate solution and extracted into ethyl acetate and after removal of the solvent 10.9 g (66%) of the title compound were obtained.

EXAMPLE 55

• a) Zu 5 g (0,0173 mol) (±)-(2-Chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitril, gelöst in 100 ml Aceton, wurden 4,35 g (0,0174 mol) (1S)-(+)-Campher-10-sulfonsäurehydrat in 5 ml Wasser in einer Charge zugegeben, wobei die Temperatur während der Zugabe bei 60°C bis 62°C gehalten wurde. Das Gemisch wurde bei 60°C 60 Stunden lang gerührt, anschließend wurde das Rühren über Nacht fortgesetzt und das Gemisch anschließend 1 Tag in einer Kühlvorrichtung aufbewahrt. Das ausgefällte diastereomere Salz wurde dann gefiltert, um 730 mg Produkt zu erhalten.
• b) Zu 730 mg (±)-(2-Chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitril-(1S)-(+)-campher-10-sulfonsäuresalz in 20 ml Wasser wurden 10 ml (5%) Na₂CO₃-Lösung gegeben (pH=10). Nach Rühren des Gemisches wurden 100 ml Ethylacetat zu der organischen Schicht gegeben. Die organische Schicht wurde dann abgetrennt und abdestilliert, um das Produkt zu erhalten. Die Produktausbeute war 400 mg (16%).

Spezifische optische Drehung (α^D): +7,5787° (C=1, DMF).Dissolution of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (IV)

• a) To 5 g (0.0173 mol) of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile dissolved in 100 ml Acetone, 4.35 g (0.0174 mol) of (1S) - (+) - camphor-10-sulfonic acid hydrate in 5 ml of water were added in one batch, maintaining the temperature at 60 ° C to 62 ° C during the addition has been. The mixture was stirred at 60 ° C for 60 hours, then stirring was continued overnight and the mixture was then stored for 1 day in a refrigerator. The precipitated diastereomeric salt was then filtered to yield 730 mg of product.
• b) To 730 mg of (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile (1S) - (+) - camphor 10-sulfonic acid salt in 20 ml of water was added 10 ml (5%) of Na ₂ CO ₃ solution (pH = 10). After stirring the mixture, 100 ml of ethyl acetate was added to the organic layer. The organic layer was then separated and distilled off to obtain the product. The product yield was 400 mg (16%).

Specific optical rotation (α ^D ): + 7.5787 ° (C = 1, DMF).

Claims (28)

Process for the preparation of a compound of formula (I),

wherein X represents hydrogen, fluoro, chloro, bromo or iodo, preferably 2-chloro, which comprises: i) reacting a compound of formula (V) or its salt

with a cyanide of general formula (VII), wherein M represents alkali metal, trimethylsilyl, Cu or hydrogen, with addition of a compound of general formula (VI), wherein X is as defined above, to form a racemic (±) compound of general formula (IV) where X is as defined above, ii) reacting a compound of general formula (IV) in (±) -form or one of its optically active (+) or (-) forms,

with an acidic or basic reagent to obtain a compound of formula (II) or its salt while maintaining the configuration, iii) reacting a compound of general formula (II) in (±) -form or one of its optically active (+) - or (-) - forms,

with an acidic reagent in the presence of methanol to obtain a compound of formula (I) or its salt, while maintaining the configuration, (iv) finally dissolving the compound of formula (I) or its salt, if in (±) - Form, to their optical isomers. The method of claim 1, further comprising the steps of of dissolution a racemic (±) compound of formula (IV) into their optical isomers and / or transforming the racemic compound or its optical isomer to theirs Salt, optionally followed by the release of the salt from the Connection. The method of claim 1, further comprising the steps of of dissolution a racemic (±) compound of formula (II) in their optical isomers and / or transforming the racemic compound or its optical isomer to theirs Salt, optionally followed by the release of the salt the connection. A process for preparing a compound of formula (III) or its salt, wherein X represents hydrogen, chloro, bromo or iodo, preferably 2-chloro, which comprises

(i) preparing a compound of general formula (IV) or its salt in one of its optical forms by a process according to step (i) of claim 1 or 2 in the presence of an acidic / basic catalyst in a suitable solvent to give the corresponding acid of formula (III) or its salt having a configuration corresponding to that of the starting material, and (ii) if desired, finally dissolving the racemic compound of formula (III) or its salt, if in racemic (±) form their corresponding optically pure (+) and (-) forms. A process according to claim 1 or 2, wherein a compound of formula (II) is (2-halophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetamide or its optically active isomers or salts thereof, wherein X represents a halogen atom such as a chloro, bromo, or iodo substituent, more preferably 2-chloro, is prepared by a process comprising

(i) treating the compound of formula (IV) or its salt or in one of its optical forms with a basic reagent when the starting material is in racemic form, or otherwise with an acidic catalyst when the starting material is in optically active form Presence of a suitable solvent and (ii) finally forming a salt of the racemic compound of formula (II) which is dissolved in its corresponding optically pure (+) or (-) forms. A method according to claim 5, which comprises the preparation of a Compound of formula (II), characterized in that the basic reagent used is lithium hydroxide, Potassium hydroxide, sodium hydroxide and potassium t-butoxide. A method according to claim 5, which comprises the preparation of a Compound of formula (II), wherein the acid catalyst used selected from the group is that made of acetic acid, p-toluenesulfonic acid, trifluoroacetic, Chloroacetic acid, perchloric acid, formic acid or mineral acids such as anhydrous alcoholic hydrogen halides or aqueous Hydrochloric acid, Sulfuric acid, HBr or a mixture thereof. A process according to claim 5, 6 or 7, which comprises preparing a compound of formula (II), wherein the solvent used is water, a (C ₁ -C ₄ ) -alcohol, acetone, acetic acid, dimethylformamide, THF, DMSO, dioxane, DME or mixtures thereof, preferably a mixture of water, methanol or tert-BuOH. Method according to one of claims 5 to 8, wherein a compound of formula (II), (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide, in the presence of a solvent such as water, acetone, ethyl acetate or a mixture thereof in theirs (-)- and (+) - forms resolved which is 1- (R) - or 1- (S) -camphorsulfonic-10-acid or Tartaric acid, in particular 1- (R) - or 1- (S) -camphorsulfonic-10-acid with the salt used optionally in a molar ratio of 0.5 to 1.1 equivalents present is. Method according to one of claims 5 to 8, wherein a compound of formula (II), (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) -acetamide, is converted into a corresponding salt selected from D-camphorsulfonate, L-camphorsulfonate, D-tartrate, L-tartrate or hydrogen sulfate. A process according to any one of claims 1 to 3 or 5 to 10, wherein the compound of formula (I) is methyl (2-halophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5 yl) acetate or its optically active isomers or its salts, wherein X represents a halogen atom, such as a chloro, bromo, or iodo substituent, more preferably 2-chloro, the process comprising

(i) treating the compound of formula (II) or its salt in racemic form or in one of its optical forms with an acidic reagent in the presence of a suitable solvent; and (ii) forming a salt of the racemic compound of formula (I) which is described in U.S. Pat their corresponding optically pure (+) or (-) forms are resolved. The method of claim 11, wherein the used acidic reagent of concentrated sulfuric acid in the range of 1 equivalent up to 50 equivalents, preferably at 0 ° C up to 5 ° C or at a reflux temperature of the solvent used selected is. The method of claim 11, wherein the used solvents methanol in the range of 3 to 30 volumes, together with an accompanying solvent such as toluene, DMSO or xylene or mixtures thereof. The method of claim 11, wherein the duration of the Treatment with an acidic reagent from 4 hours to 4 days is enough. The method of claim 11, wherein the reaction in a temperature in the range of 40 ° C to 140 ° C is performed. The method of claim 11, wherein a racemic Compound of formula (I) using 1- (R) - or 1- (S) -camphorsulfonic-10-acid, (R) - or (S) -tartaric acid, especially 1- (R) - or 1- (S) -camphorsulfone-10-acid, in the presence of a solvent such as water, acetone, ethyl acetate or a mixture thereof. The method of claim 16, wherein a mixture with different proportions the two enantiomers (-) - I and (+) - I chirally enriched to the (+) - (I) stereoisomer, or the (-) - (I) enantiomer becomes chiral from a variable mixture of (-) - I and (+) - I stereoisomers away. Process for preparing a compound of formula (IV) or its salt,

wherein X represents a halogen atom such as chloro, bromo or iodo, in particular 2-chloro, which comprises: i) reacting a compound of formula (V) or its acid addition salt with a cyanide of general formula (VII), wherein the meaning of M is alkali metal , TMS, Cu or hydrogen, followed by reaction with a halobenzaldehyde of formula (VI) wherein X is a halogen atom, and dissolving the product into its optical isomers and, if desired, its release from its salt or its trans formation of its salt, or (ii) reacting a halobenzaldehyde of the general formula (VI) wherein the meaning of X is halogen atom, with a cyanide of the general formula (VII) wherein M is as defined above, followed by in situ -Addition of the compound of formula (V) or its acid addition salt, or (iii) reacting a halobenzaldehyde of the general formula (VI), wherein the meaning of X is halogen atom, with a hydrogen sulfite of the general formula M'HSO ₃ (VIII), wherein M 'is sodium, potassium or lithium, and finally with a cyanide of general formula (VII), wherein M is as defined above, and then reacting in situ with the compound of general formula (V) or its acid addition salt; and (iv) finally dissolving the resulting compound of formula (IV) or its salt to its optically pure (+) and (-) form of the compound of formula (IV) or its salt. The method of claim 18, wherein the reaction in a temperature between 0 ° C and 100 ° C carried out will, except that the reaction temperature can drop further to -30 ° C if it is at MCN is HCN gas. The method of claim 18 or 19, wherein the reaction in an aqueous or a non-aqueous one Medium performed which becomes an acid such as acetic acid or propionic acid, Contains methanol and HCl / MeOH. A process according to any one of claims 18 to 20, wherein a catalyst acid such as for example, dry hydrochloric acid, Sulfuric acid, p-toluenesulfonic acid or acetic acid is used. A method according to any one of claims 18 to 21, wherein the compound of formula (IV), (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile, in the presence of acetone, ethyl acetate or a mixture thereof and Water in their (-) - and (+) - forms resolved is 1- (R) - or 1- (S) -camphorsulfonic-10-acid or tartaric acid, in particular 1- (R) - or 1- (S) -camphorsulfone-10-acid is used. A method according to any one of claims 18 to 21, wherein a compound of formula (IV), (±) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetonitrile, in (±) - or (-) - or (+) - form is converted into its salt, the claimed Salt D-camphorsulfonate, L-camphorsulfonate, D-tartrate, L-tartrate or hydrogen sulfate. A method according to any one of claims 18 to 23, wherein the racemization of the (-) isomer the compound of formula (II) in a mixture containing the (+) stereoisomer may contain the (±) connection too obtained using a base such as LDA, KOH, NaOH, Kt BuOH, NaOMe, NaH or KH is carried out in a suitable solvent. The method of claim 1, wherein the racemization of the (-) isomer the compound of formula (I) in a mixture containing the (+) stereoisomer may contain the (±) connection using a base such as LDA, NaOMe, NaH, KH in a suitable solvent carried out becomes. The method of claim 17, wherein the resolution in Presence of acetone as solvent in the range of 5 to 10 volumes, containing up to 5% water can, performed becomes. The method of claim 17, wherein the appropriate chiral agents in a molar ratio of 1: 1 is used. The method of claim 27, wherein the temperature from 0 ° C to the reflux temperature of the solvent is.